Leveraging Extraction Testing to Predict Patient Exposure to Polymeric Medical Device Leachables Using Physics-based Models

Abstract

Toxicological risk assessment approaches are increasingly being used in lieu of animal testing to address toxicological concerns associated with release of chemical constituents from polymeric medical device components. These approaches currently rely on in vitro extraction testing in aggressive environments to estimate patient exposure to these constituents, but the clinical relevance of the test results is often ambiguous. Physics–based mass transport models can provide a framework to interpret extraction test results to provide more clinically relevant exposure estimates. However, the models require system–specific material properties, such as diffusion (D) and partition coefficients (K), to be established a priori for the extraction conditions. Using systems comprised of high–density polyethylene and four different additives, we demonstrate that these properties can be quantified through standard extraction testing in hexane and isopropyl alcohol. The values of D and K derived in this manner were consistent with theoretical predictions for these quantities. Based on these results, we discuss both the challenges and benefits to leveraging extraction data to parameterize physics–based exposure models. Our observations suggest that clinically relevant, yet still conservative, exposure dose estimates provided by applying this approach to a single extraction measurement can be more than 100 times lower than would be measured under typical aggressive extraction conditions. However, to apply the framework on a routine basis, limiting values of D and K must be established for device–relevant systems either through the aggregation and analysis of more extensive extraction test data and/or advancements in theoretical and computational modeling efforts to predict these quantities.

Relations Between Dynamic Localization and Solute Diffusion in Polymers

“…To address these challenges, recent work has been aimed at developing physics-based transport models to rapidly provide more clinically relevant exposure estimates. ,− These models can be used to predict the release rate of leachable chemicals from device materials over time by modeling physical processes like diffusion, fluid flow, and chemical reactions. Each of these processes requires system-specific material parameters to be established, such as the diffusivity D of a solute in a polymer when modeling diffusive flux.…”

“…Alternative methods to quantify or estimate D more rapidly have been developed. Several semi-empirical approaches based on free-volume theories are available, such as the Wilke–Chang and Vrentas–Duda models. − We recently compared predictions from these models with values of D obtained from extraction experiments, and we found good agreement under reasonable assumptions . However, these semi-empirical relations generally require experimental data to determine appropriate values for their numerous parameters, and these parameters may not be transferable between material systems.…”

“…However, these semi-empirical relations generally require experimental data to determine appropriate values for their numerous parameters, and these parameters may not be transferable between material systems. Moreover, while in some cases the parameters can be estimated based on molecular structure or readily available physical properties (e.g., density), , in general, they remain challenging to estimate a priori . Last, although free-volume theories succeed with the smallest solutes (e.g., gases), they become less reliable with larger molecules where structural relaxations become important. , …”

“…Moreover, while in some cases the parameters can be estimated based on molecular structure or readily available physical properties (e.g., density), , in general, they remain challenging to estimate a priori . Last, although free-volume theories succeed with the smallest solutes (e.g., gases), they become less reliable with larger molecules where structural relaxations become important. , …”

“…The diffusion of small solutes in polymers plays a role in a variety of applications, such as food packaging safety, 1 controlled drug delivery, 2 and medical device biocompatibility. 3 Polymeric components in medical devices typically contain trace amounts of small and potentially hazardous molecules, including additives to improve polymer performance along with manufacturing byproducts and contaminants. When a device contacts a patient, these solutes may leach into the body and therefore may present a public health concern.…”